肿瘤细胞治疗研究
英文原题：Synthesis and preclinical evaluation of tigilanol tiglate analogs as latency-reversing agents for the eradication of HIV.
Tigilanol tiglate（EBC-46）是一种蛋白激酶C（PKC）亚型的选择性调节剂，已获美国食品药品监督管理局（FDA）批准用于治疗犬肥大细胞瘤，治愈率高达88%。
Tigilanol tiglate（EBC-46）是一种蛋白激酶C（PKC）亚型的选择性调节剂，已获美国食品药品监督管理局（FDA）批准用于治疗犬肥大细胞瘤，治愈率高达88%。近期，它已获FDA批准用于治疗人类软组织肉瘤。EBC-46及其类似物在清除HIV、治疗神经和心血管疾病，或增强抗原靶向CAR-T 细胞和嵌合抗原受体NK 细胞免疫疗法中抗原密度方面的作用尚未有报道。借助我们此前报道的EBC-46可规模化合成方法，我们在此报道了EBC-46类似物的系统性设计、合成与评估，包括那些无法从天然来源获得的类似物，以及它们的PKC亲和力、转位PKC的能力、核因子κB活性，以及在Jurkat-Latency细胞中逆转HIV潜伏的有效性。领先的类似物表现出卓越的PKC亲和力、亚型选择性和功能活性，有望成为治疗应用的候选药物。
Tigilanol tiglate (EBC-46) is a selective modulator of protein kinase C (PKC) isoforms that is Food and Drug Administration (FDA) approved for the treatment of mast cell tumors in canines with up to an 88% cure rate. Recently, it has been FDA approved for the treatment of soft tissue sarcomas in humans. The role of EBC-46 and, especially, its analogs in efforts to eradicate HIV, treat neurological and cardiovascular disorders, or enhance antigen density in antigen-targeted chimeric antigen receptor-T cell and chimeric antigen receptor-natural killer cell immunotherapies has not been reported. Enabled by our previously reported scalable synthesis of EBC-46, we report herein the systematic design, synthesis, and evaluation of EBC-46 analogs, including those inaccessible from the natural source and their PKC affinities, ability to translocate PKC, nuclear factor κB activity, and efficacy in reversing HIV latency in Jurkat-Latency cells. Leading analogs show exceptional PKC affinities, isoform selectivities, and functional activities, serving as promising candidates for therapeutic applications.
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